| Structural highlights
Disease
[GALE_HUMAN] Defects in GALE are the cause of epimerase-deficiency galactosemia (EDG) [MIM:230350]; also known as galactosemia type 3. Clinical features include early-onset cataracts, liver damage, deafness and mental retardation. There are two clinically distinct forms of EDG. (1) A benign, or 'peripheral' form with no detectable GALE activity in red blood cells and characterized by mild symptoms. Some patients may suffer no symptoms beyond raised levels of galactose-1-phosphate in the blood. (2) A much rarer 'generalized' form with undetectable levels of GALE activity in all tissues and resulting in severe features such as restricted growth and mental development.[1] [2] [3] [4] [5] [6] [7] [8]
Function
[GALE_HUMAN] Catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine.
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
UDP-galactose 4-epimerase catalyzes the interconversion of UDP-glucose and UDP-galactose during normal galactose metabolism. In humans, deficiencies in this enzyme lead to the complex disorder referred to as epimerase-deficiency galactosemia. Here, we describe the high-resolution X-ray crystallographic structures of human epimerase in the resting state (i.e., with bound NAD(+)) and in a ternary complex with bound NADH and UDP-glucose. Those amino acid side chains responsible for anchoring the NAD(+) to the protein include Asp 33, Asn 37, Asp 66, Tyr 157, and Lys 161. The glucosyl group of the substrate is bound to the protein via the side-chain carboxamide groups of Asn 187 and Asn 207. Additionally, O(gamma) of Ser 132 and O(eta) of Tyr 157 lie within 2.4 and 3.1 A, respectively, of the 4'-hydroxyl group of the sugar. Comparison of the polypeptide chains for the resting enzyme and for the protein with bound NADH and UDP-glucose demonstrates that the major conformational changes which occur upon substrate binding are limited primarily to the regions defined by Glu 199 to Asp 240 and Gly 274 to Tyr 308. Additionally, this investigation reveals for the first time that a conserved tyrosine, namely Tyr 157, is in the proper position to interact directly with the 4'-hydroxyl group of the sugar substrate and to thus serve as the active-site base. A low barrier hydrogen bond between the 4'-hydroxyl group of the sugar and O(gamma) of Ser 132 facilitates proton transfer from the sugar 4'-hydroxyl group to O(eta) of Tyr 157.
Crystallographic evidence for Tyr 157 functioning as the active site base in human UDP-galactose 4-epimerase.,Thoden JB, Wohlers TM, Fridovich-Keil JL, Holden HM Biochemistry. 2000 May 16;39(19):5691-701. PMID:10801319[9]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Timson DJ. Functional analysis of disease-causing mutations in human UDP-galactose 4-epimerase. FEBS J. 2005 Dec;272(23):6170-7. PMID:16302980 doi:10.1111/j.1742-4658.2005.05017.x
- ↑ Maceratesi P, Daude N, Dallapiccola B, Novelli G, Allen R, Okano Y, Reichardt J. Human UDP-galactose 4' epimerase (GALE) gene and identification of five missense mutations in patients with epimerase-deficiency galactosemia. Mol Genet Metab. 1998 Jan;63(1):26-30. PMID:9538513 doi:S1096-7192(97)92645-7
- ↑ Thoden JB, Wohlers TM, Fridovich-Keil JL, Holden HM. Molecular basis for severe epimerase deficiency galactosemia. X-ray structure of the human V94m-substituted UDP-galactose 4-epimerase. J Biol Chem. 2001 Jun 8;276(23):20617-23. Epub 2001 Mar 7. PMID:11279193 doi:10.1074/jbc.M101304200
- ↑ Quimby BB, Alano A, Almashanu S, DeSandro AM, Cowan TM, Fridovich-Keil JL. Characterization of two mutations associated with epimerase-deficiency galactosemia, by use of a yeast expression system for human UDP-galactose-4-epimerase. Am J Hum Genet. 1997 Sep;61(3):590-8. PMID:9326324 doi:S0002-9297(07)64322-5
- ↑ Wohlers TM, Christacos NC, Harreman MT, Fridovich-Keil JL. Identification and characterization of a mutation, in the human UDP-galactose-4-epimerase gene, associated with generalized epimerase-deficiency galactosemia. Am J Hum Genet. 1999 Feb;64(2):462-70. PMID:9973283 doi:S0002-9297(07)61751-0
- ↑ Henderson JM, Huguenin SM, Cowan TM, Fridovich-Keil JL. A PCR-based method for detecting known mutations in the human UDP galactose-4'-epimerase gene associated with epimerase-deficiency galactosemia. Clin Genet. 2001 Nov;60(5):350-5. PMID:11903335
- ↑ Park HD, Park KU, Kim JQ, Shin CH, Yang SW, Lee DH, Song YH, Song J. The molecular basis of UDP-galactose-4-epimerase (GALE) deficiency galactosemia in Korean patients. Genet Med. 2005 Nov-Dec;7(9):646-9. PMID:16301867 doi:10.109701.gim.0000194023.27802.2d
- ↑ Wasilenko J, Lucas ME, Thoden JB, Holden HM, Fridovich-Keil JL. Functional characterization of the K257R and G319E-hGALE alleles found in patients with ostensibly peripheral epimerase deficiency galactosemia. Mol Genet Metab. 2005 Jan;84(1):32-8. PMID:15639193 doi:S1096-7192(04)00242-2
- ↑ Thoden JB, Wohlers TM, Fridovich-Keil JL, Holden HM. Crystallographic evidence for Tyr 157 functioning as the active site base in human UDP-galactose 4-epimerase. Biochemistry. 2000 May 16;39(19):5691-701. PMID:10801319
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